Cross-presentation of exogenous antigens to cytolytic T cells (CTL) by dendritic cells (DC) relies on the major cellular proteolysis machinery, the proteasome, to digest long polypeptides into small fragments, which can associate with cell surface molecules (MHC class I) which form the specific ligands that trigger T-cell activation. In contrast, presentation of exogenous antigens to helper T-lymphocytes (HTL) by dendritic cells primarily depends on the lysosomal pathway; proteases inside lysosomes contribute to the digestion of internalized proteins and digested small peptide fragments are then loaded on MHC class II molecules to activate naïve HTL.
Tumor cells process antigens that can be recognized by T lymphocytes (T cells) and activated cytolytic T cells (CTL) that constantly circulate and seek to destroy tumor cells (Hu, H. M., Chu, Y. & Urba, W. J. Undefined-antigens as vaccines. Cancer Treatment and Research (ed Kheif, S.) 207-226, Kluwer Academic Publishers, New York, 2005). Therefore, methods of treating cancer using cancer immunotherapy have been proposed to generate therapeutic T cells that are reactive to tumor-associated antigens above the threshold level required to mediate regression of established tumors and prevent tumor recurrence.
Unfortunately, despite considerable effort by many investigators for many years, specific active immunization with cancer vaccines has not been very effective in animal models or in clinical trials (Rosenberg et al., Nat. Med. 10:909-15, 2004). The primary obstacle to the success of cancer immunotherapy has been the inability of the vaccine to induce initially a large expansion and then persistence of tumor-reactive CTL (Rosenberg et al., Nat. Med. 10:909-15, 2004). Another obstacle to currently available methods of cancer immunotherapy is that potential tumor rejection antigens are not known for most cancers, with the exception of melanoma, and the dominant tumor rejection antigens are likely tumor or patient-specific.
Although various strategies have been developed in recent years, including gene-modified tumor vaccines, heat shock proteins derived from tumors, dendritic cells loaded with tumor lysates or transfected with tumor derived RNA, fusion of tumor and dendritic cells; and exosomes secreted from tumor cells, their ability to induce a high level of tumor-specific T cells in tumor-bearing hosts has yet to be demonstrated. Therefore, new immunogenic approaches are needed for the treatment of cancer.